Project Summary The Candidate The Candidate for this K01 award, Dr. Yuanyuan Li, is an Instructor in the Division of Hematology and Oncology of the Department of Medicine at the University of Alabama at Birmingham (UAB). Dr. Li started her research studies in dietary epigenetic cancer research under the direction of Dr. Trygve Tollefsbol, the primary Mentor of this K01 award, since 2006. Dr. Li's research interest centers on exploring the molecular epigenetic mechanisms of disease initiation and discovering potential interactions between epigenetic regulations and environmental impacts on human disease development and susceptibility. Dr. Li has established remarkable research contributions as a result of her significant of publications and research awards in the area. Dr. Yuanyuan Li is committed to acquire necessary training, practical experience and knowledge to become an independent research investigator. During the first two years of the award, she will focus on building up her research publication record and improving her skills in scientific writing including research articles and grant applications. From the third year of this K01 award, Dr. Li will actively seek long- term funding support that will allow her to become a fully independent investigator after completion of this K01 award. Dr. Li's long-term career goal is to establish an innovative and independent research program to understand how genes and environment interact to influence disease development, and to explore novel dietary intervention regimens for early disease prevention. Institutional Environment UAB is one of the top research institutions in the U.S. and has outstanding resources for trainees. There are state of the art laboratories for work in basic and clinical research and outstanding core facilities for supporting molecular and clinical research activities. The candidate's more immediate research environment is the Department of Biology and Wallace Tumor Institute (WTI) in the Division of Hematology and Oncology of the Department of Medicine at UAB. The candidate is a member of the UAB Comprehensive Cancer Center (CCC) and the Nutrition Obesity Research Center (NORC), both of which will provide additional resources and infrastructure that will facilitate the completion of this project. Research Summary The etiology of most human diseases involves complicated interactions of multiple environmental factors with individual genetic background which is initially generated early in human life, for example, during the processes of embryogenesis and fetal development in utero. Maternal exposure to certain diets with properties in influencing epigenetic processes may influence the epigenetic reprograming processes during early embryogenesis, which may consequently influence gene expression patterns and eventually affect phenotype outcome in the offspring such as differences in disease susceptibility. The bioactive dietary components, sulforaphane (SFN), an isothiocyanate enriched in cruciferous vegetables such as broccoli sprouts (BSp), and genistein (GE) in soybean products are strong epigenetic modulators and robust chemopreventive agents against various human diseases such as cancers and obesity-related diseases in vitro and in vivo. We now have compelling evidence showing that maternal dietary BSp or GE treatments influence offspring susceptibility to diseases and metabolic disorders such as breast cancer and obesity in adult life. We hypothesize that BSp or GE bioactive natural plant products impact early embryonic development by affecting epigenetic profiles resulting in different susceptibility to breast cancer and metabolic disorders such as obesity later in life. The specific aims of this proposal are therefore to 1) determine the temporal effects of early BSp or GE administration on development of breast cancer and obesity in mouse models, 2) evaluate gene expression and epigenetic alterations of specific epigenetic-controlled genes in response to early BSp or GE treatment and 3) assess the impacts of maternal BSp or GE diet on epigenomic profiles including methylome and acetylome alterations as well as determination of key candidate epigenetic genes in control of early disease chemoprevention by this regimen. The goal of this proposal is to determine the effectiveness of maternal BSp and GE diets on early-life disease intervention and the potential epigenetic mechanisms. This study may lead to translational disease chemoprevention potential that benefits human health by appropriate administration of prenatal and/or postnatal dietary supplements leading to early prevention of multiple human diseases including breast cancer, obesity and obesity-related human diseases. The Candidate anticipates being able to complete the studies within a five-year award period through collaborative efforts with her Mentors and collaborators.